Retinitis pigmentosa is a collection of inherited retinal degenerations affecting 50,000 to 100,000 individuals in the United States. Over the past decade, much progress has been made in identifying disease-causing genetic mutations. However, little is known about the mechanisms by which these mutations trigger photoreceptor cell death, making development of effective therapies difficult. The long-term objective of these studies is to identify molecular triggers of photoreceptor cell death. Specifically, these studies will test the hypothesis that genetic mutations that affect the signaling efficiency of rhodopsin cause retinal degeneration. The role of transducin signaling in retinal degenerative disease will be tested using signal-defective transgenic mice with a knock-out of the rod alpha-transducin gene. These mice will be used to test two proposed specific aims. Specific aim 1 will test the hypothesis that some rhodopsin mutations cause degeneration by the constitutive activation of transducin signaling, akin to retinal damage induced by continuous light exposure in rodents. Specific aim 2 will test the hypothesis that the opsin apoprotein, which may accumulate with defective rhodopsin regeneration, generates a signal that causes degeneration. To achieve these goals, rhodopsin mutant mice and opsin-producing transgenic mice will be crossed to transducin knock-out mice. Specific aim 3 will test the hypothesis that increase or decrease in rhodopsin density, which affects the efficiency of rhodopsin signaling, causes retinal degeneration. Levels of rhodopsin required to maintain normal retinal morphology, the time at which rhodopsin must be expressed to rescue degeneration, and how increased levels of wild type rhodopsin on a rhodopsin mutant background affects the severity of retinal degeneration will be defined. Specific aim 3 will be accomplished using transgenic mice with drug-inducible rhodopsin expression. The results of these studies could lead to the development of rational gene therapies for the treatment of RP and other retinal degenerations.